'When you hear hoofbeats, think of horses not zebras' - the old adage is well-known to GPs but what should you do when faced with a zebra, not a horse? Consultant cardiologist Professor Robert Tulloh and GP Dr Louise Tulloh kick off our new series with their advice on how to catch Kawasaki disease in general practice.

Ten top tips - NOACs

1. Know the differences between the NOACs

The NOACs are new oral anticoagulants, or sometimes called non-vitamin K antagonist (VKA) oral anticoagulants (since they are no longer that new). There are four NOACs currently licensed for use in the UK:

Dabigatran

Apixaban

Rivaroxaban

Edoxaban

Brand name

Pradaxa

Eliquis

Xarelto

Lixiana

Mechanism of action

Direct thrombin inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Dose in non-valvular AF*

150mg BD

5mg BD

20mg OD

60mg OD

Reduced dose in renal impairment**/elderly/body weight <60kg

110mg BD

2.5mg BD

15mg OD

30mg OD

Renal elimination

80%

25%

33%

35%

Specific reversal agent

Yes (Idarucizumab)

No (Octaplex sufficient)

No (Octaplex sufficient)

No (Octaplex sufficient)

Cost per annum

£620.50

£693.50

£657.00

£675.25

*different dosing regimes are indicated depending on the indication.

**Each NOAC has specific guidance on dose adjustment depending on creatinine clearance and in some cases other factors such as age and body weight.

For comparison regarding cost, warfarin is a variable dose that can require different combinations of tablets with a cost in the region of £25 per annum. The cost of INR monitoring varies depending on the local model, but is in the region of £150 per year for the hospital INR outpatient model, £190 for satellite clinics, or £330 for home INR monitoring.

2. Be clear on the indications for the NOACs

By far the most common use is for non-valvular AF (by which people mean not rheumatic valve disease or metallic valve replacements where people still use warfarin). They should be offered first line alongside warfarin.

They are also licensed for venous thromboembolism prophylaxis following hip or knee surgery as well as treatment of deep vein thrombosis and venous thromboembolism.

Rivaroxaban is also licensed as prophylaxis of atherothrombotic events following acute coronary syndrome in combination with dual antiplatelet therapy.

3. Switch patients on warfarin with difficult to control INR to a NOAC

The NOACs have each undergone a single large randomised controlled trial comparing them to warfarin in the context of AF and they have all been shown to be at least as effective as warfarin in prevention of thromboembolic stokes and at least as safe as warfarin. There is a tendency towards lower rates of bleeding with NOACs, in particular intracerebral bleeding. Overall mortality was actually lower for both apixaban and edoxaban compared to warfarin.

Patients on warfarin who have difficult to control INR or have a time-in-therapeutic range of <65% derive little, if any, benefit from warfarin and are at increased risk of bleeding. These patients have the most to gain from changing to a NOAC and it is poor practice to continue with warfarin in these patients nowadays. There are ongoing studies looking at identifying patients who would benefit from changing from warfarin to a NOAC.

4. Take an individualised approach to starting patients on NOACs

We would advocate an individual approach to each patient in whom you start a NOAC – taking into account their age, renal function, comorbidities, current medications and risk of bleeding. Rivaroxban and edoxaban are once daily medications, which might make them easier for some patients to adhere to. As dabigatran has a predominantly renal mode of excretion, it would be better to choose another NOAC in patients with moderate renal impairment.

In reality, many doctors become comfortable prescribing one or two NOACs and then stick to what they are familiar with. Given that the evidence is similar for each, this seems very reasonable.

5. Remember to check renal function.

All NOACs are excreted renally to some extent and they all have dose adjustments according to renal function. Dabigatran is contraindicated if creatinine clearance is <30ml/min and the others are contraindicated at <15ml/min. It is best to look up specific indications for dose reduction in each NOAC as they differ slightly for each. Realistically, the creatinine clearance will fluctuate a little, so if the GFR is <30 ml/min, many physicians choose not to prescribe a NOAC and stick with warfarin.

6. Be aware of contraindications and interactions when starting NOACs

Patients with ‘valvular AF’ (including rheumatic heart disease or those with metal valves) should take warfarin rather than a NOAC. Patients with severe renal impairment and those on renal replacement therapy cannot take NOACs.

Severe liver disease and cirrhosis is a contraindication to either warfarin or a NOAC. A high bleeding risk and advanced malignancy really rules out both also. Falls are rarely a real contraindication to anticoagulation. Modelling suggests that on average, one would have to fall over almost daily for one’s risk of harm from falls to exceed the risk from thromboembolic stroke.

Like warfarin, NOACs are known to be affected by certain enzyme inducers and inhibitors and there are therefore certain drug interactions that can affect the dose or whether the drug ought to be used. This includes drugs such as verapamil, amiodarone and dronedarone, which are frequently used in patients with AF – check the BNF when prescribing.

7. Be aware of how to manage bleeding

Bleeding is of course a risk with all oral anticoagulants. However, trial data suggests that there is a trend towards lower bleeding rates with NOACs compared to warfarin, in particular decreased rates of intracerebral haemorrhage. Management of bleeding is straight forward if it does occur. Dabigatran has a specific reversal agent (idarucizumab) that is kept in A&E departments and rapidly and completely reverses its effect. The other NOACs are completely reversible by giving clotting factors such as Octaplex (as you would for warfarin). NOACs are also much more straightforward to start and stop following bleeds or planned operations because of their rapid onset and offset.

8. Check baseline screening tests annually

The effects of NOACs are much more predictable than those of warfarin so no monitoring is necessary. Conventional clotting studies, including INR, are not reliable markers of anticoagulation and so are not useful.

A baseline FBC, U&E, LFT and clotting screen should be performed prior to starting treatment and then FBC, U&E and LFT should be checked annually to ensure patients have not developed any contraindications to NOACs or anticoagulation in general.

Renal function should be monitored more closely in patients with known impairment and in patients with an intercurrent illness that may affect renal or liver function.

9. Consider the overall cost when weighing up the benefit of NOACs over warfarin

The annual cost of NOACs is higher compared to warfarin, although there is some cost modelling suggesting that by the time one has accounted for INR monitoring, the difference is in fact fairly small (see table above). This cost also assumes equivalence and takes no account of the lower rates of intracerebral haemorrhage with NOACs, lower rates of stroke (apixaban, edoxaban, dabigatran), and lower overall mortality (apixaban and edoxaban).

10. Use the CHA2DS2-VASc system to determine stroke risk in AF patients

The CHA2DS2-VASc scoring system is currently recommended. Patients score a point for congestive heart failure, hypertension, age ≥ 75 years (two points), diabetes, stroke (two points), vascular disease (either peripheral or coronary), age ≥ 65 years and female sex.

Patients with a score of zero are low risk and do not require anticoagulation. Patients do not score a point for female sex alone (in the absence of other points). Antiplatelets have little if any effect in AF and should not be used. Anticoagulation is advised for those with a score ≥1. As a rule of thumb, the stroke risk as a percentage per year is approximately equal to the CHA2DS2 VASc score. This usually sounds small to patients but is annualised, so the risk over a five year period is at least five times this number. For example a CHA2DS2-VASc score of two gives an annualised stroke rate of approximately 2%, which equates to one in 10 over five years.

Dr Kim On is a GP trainee in Berkshire

Dr Lan-Anh Hunter is a GPSI in cardiology in Berkshire

Dr Ross J Hunter is a consultant cardiologist specialising in heart rhythm management and is the AF lead at the Barts Heart Centre, London

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Readers' comments (2)

Useful article. Thanks. Creatinine Clearance. Do we use ideal body weight or actual body weight in the calculation? In overweight patients you can get very different results depending on which you use.